Impact of Inhibitor Size and Flexibility on the Binding Pathways to c-Src Kinase.
7 affiliations
- 1RIKEN Center for Biosystems Dynamics Research, 7-1-26 minatojima-minamimachi, Chuo-ku, Kobe, Hyogo650-0047, Japan.
- 2Premium Research Institute for Human Metaverse Medicine (WPI-PRIMe), The University of Osaka, 2-8 Yamadaoka, Suita, Osaka, 565-0871, Japan.
- 3Artificial Intelligence Center for Health and Biomedical Research, National Institutes of Biomedical Innovation, Health, and Nutrition, 3-17 Senrioka Shinmachi, Settu-shi, Osaka566-0002, Japan.
- 4University of Hyogo, Graduate School of Science, 3-2-1 Kouto, Kamigori-cho, Ako-gun, Hyogo678-1297, Japan.
- 5Theoretical Molecular Science Laboratory, RIKEN Pioneering Research Institute, 2-1 Hirosawa, Wako, Saitama351-0198, Japan.
- 6RIKEN Center for Computational Science, 7-1-26 minatojima-minamimachi, Chuo-ku, Kobe, Hyogo650-0047, Japan.
- 7Department of Physics, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo113-0033, Japan.
Abstract
The conformational plasticity of protein kinases poses a challenge for inhibitor design, motivating the use of molecular dynamics (MD) simulations to study their dynamic binding processes. While conformational changes are increasingly discussed, the impact of drug compound flexibility remains underexplored because of experimental limitations. In this study, we employ two-dimensional replica-exchange MD simulations to investigate how c-Src kinase binds to PP1, a small inhibitor, and to dasatinib, a larger, more flexible inhibitor. Simulations totaling 600 μs revealed frequent binding and unbinding events, yielding statistically converged information about the binding pathways. While both inhibitors follow multiple binding pathways, a notable difference emerges in their binding mechanisms on the free-energy profiles: PP1 is rigid along the binding path, whereas dasatinib substantially changes its conformation at different stages in the pathway to the canonical pose. Conformational analysis reveals distinct conformers of dasatinib, including a hidden intermediate, which helps to avoid trapping at the salt-bridge pair linking the β3 strand and the αC-helix of the c-Src kinase. These results, distinct from previous computational studies, demonstrate that inhibitor size and flexibility affect binding mechanisms and have implications on kinetics.
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BibTeX
@article{shinobu2026impact,
title = {{Impact of Inhibitor Size and Flexibility on the Binding Pathways to c-Src Kinase.}},
author = {Ai Shinobu and Suyong Re and Hiraku Oshima and Yuji Sugita},
journal = {The journal of physical chemistry letters},
year = {2026},
month = oct,
doi = {10.1021/acs.jpclett.6c02620},
url = {https://europepmc.org/article/MED/42917142},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Impact of Inhibitor Size and Flexibility on the Binding Pathways to c-Src Kinase.
AU - Ai Shinobu
AU - Suyong Re
AU - Hiraku Oshima
AU - Yuji Sugita
PY - 2026
DA - 2026/10/01
JO - The journal of physical chemistry letters
DO - 10.1021/acs.jpclett.6c02620
UR - https://europepmc.org/article/MED/42917142
AB - The conformational plasticity of protein kinases poses a challenge for inhibitor design, motivating the use of molecular dynamics (MD) simulations to study their dynamic binding processes. While conformational changes are increasingly discussed, the impact of drug compound flexibility remains underexplored because of experimental limitations. In this study, we employ two-dimensional replica-exchange MD simulations to investigate how c-Src kinase binds to PP1, a small inhibitor, and to dasatinib, a larger, more flexible inhibitor. Simulations totaling 600 μs revealed frequent binding and unbinding events, yielding statistically converged information about the binding pathways. While both inhibitors follow multiple binding pathways, a notable difference emerges in their binding mechanisms on the free-energy profiles: PP1 is rigid along the binding path, whereas dasatinib substantially changes its conformation at different stages in the pathway to the canonical pose. Conformational analysis reveals distinct conformers of dasatinib, including a hidden intermediate, which helps to avoid trapping at the salt-bridge pair linking the β3 strand and the αC-helix of the c-Src kinase. These results, distinct from previous computational studies, demonstrate that inhibitor size and flexibility affect binding mechanisms and have implications on kinetics.
SN - 1948-7185
ER -